title: BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway.
abstract: Bone morphogenetic proteins (BMPs) are known to induce ectopic bone. However, it is largely unknown how BMP signaling in osteoblasts directly regulates endogenous bone. This study investigated the mechanism by which BMP signaling through the type IA receptor (BMPR1A) regulates endogenous bone mass using an inducible Cre-loxP system. When BMPR1A in osteoblasts was conditionally disrupted during embryonic bone development, bone mass surprisingly was increased with upregulation of canonical Wnt signaling. Although levels of bone formation markers were modestly reduced, levels of resorption markers representing osteoclastogenesis were severely reduced, resulting in a net increase in bone mass. The reduction of osteoclastogenesis was primarily caused by Bmpr1a-deficiency in osteoblasts, at least through the RANKL-OPG pathway. Sclerostin (Sost) expression was downregulated by about 90% and SOST protein was undetectable in osteoblasts and osteocytes, whereas the Wnt signaling was upregulated. Treatment of Bmpr1a-deficient calvariae with sclerostin repressed the Wnt signaling and restored normal bone morphology. By gain of Smad-dependent BMPR1A signaling in mice, Sost expression was upregulated and osteoclastogenesis was increased. Finally, the Bmpr1a-deficient bone phenotype was rescued by enhancing BMPR1A signaling, with restoration of osteoclastogenesis. These findings demonstrate that BMPR1A signaling in osteoblasts restrain endogenous bone mass directly by upregulating osteoclastogenesis through the RANKL-OPG pathway, or indirectly by downregulating canonical Wnt signaling through sclerostin, a Wnt inhibitor and a bone mass mediator.
authors.affiliation: Laboratory of Reproductive and Developmental Toxicology, NIEHS/NIH, Research Triangle Park, NC 27709, USA.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kamiya
authors.forename: Ling
authors.initials: L
authors.lastname: Ye
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mochida
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015415:Biomarkers; D015519:Bone Density / Q000502:physiology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D001842:Bone and Bones / Q000033:anatomy & histology*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers / Q000235:genetics; D006023:Glycoproteins; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D009928:Organ Specificity; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D024042:Collagen Type I; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; C486030:Sost protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D051153:Wnt Proteins; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; C045073:Cre recombinase; D019426:Integrases